Process for preparing o, s-disubstituted thiol-type thiamine derivatives



United States Patent 0 The present invention relates to a process for preparing O,S-disubstituted thiol-type thiamine derivatives represented by the formula:

s-ooon wherein R and R are each an alkyl group having not more than five carbon atoms (e.g. methyl, ethyl, propyl, butyl) or an alkenyl group having not more than five carbon atoms (e.g. allyl, crotyl). [The partial structure encompassed by the dotted line in the above formula will be hereinafter summarized as Thia.]

The said O,S-disubstituted thiol-type thiamine derivatives (I) and non-toxic salts thereof possess vitamin B activity. It is noted that, when orally administered, these compounds are rapidly absorbed from the intestinal canal and a high concentration of vitamin B in the blood is maintained for a long time.

The said O,S-disubstit-uted thiol-type thiamine derivatives (I) have heretofore been prepared by the following two methods:

Method A SMet. S--C-OOR ol-co 0R 'llna Thla Basic catalyst C HzCH O-H in organic solvent CH2CH20C O O R Method B S-Met. S-COOR Cl- C 00 R Thia 'lhla in water CH 20112-0 H CH2CH20-H S O 00 R 01-0 0 O R Thia in organic solvent wherein Met. is an alkali metal (e.g. sodium, potassium) and R and R have each the same significance as designated above. Of these methods, the method (B) affords the objective O,S-disubstituted thiol-type thiamine derivatives (1) in better yields than the method (A), although the former requires two steps. As well known, however, thiol-type thiamine and its derivatives are relatively unstable in a basic medium, and the use of a basic catalyst in the methods (A) and (B) results in unavoidable contamination of the product with the impurities produced by decomposition of the starting material, the intermediate and/ or the product whereby somewhat difiicult purification is caused.

There has now been discovered that O-(a-tetrahydrm pyranyD-S-Substituted thiol-type thiamine derivatives represented by the formula:

S-COOR Patented Apr. 4, 1967 wherein R has the same significance as designated above react with phosgene in an organic solvent whereby the m-tetrahydropyranyl group at the O-position is replaced by a chlorocarbonyl group to give O-chlorocarbonyl-S-substituted thiol-type thiamine derivatives represented by the formula:

S-O O 0 R Thia ornorn0-coo1 (III) wherein R has the same significance as designated above. There has also been discovered that the thus-prepared O-chlorocarbonyl-S-substituted thiol-type thiamine derivatives (III) react with an alkanol or alkenol to give the objective O,S-disubstituted thiol-type thiamine derivatives (I). The present invention is substantially based on the discoveries.

The process of the present invention is represented by the following formulae:

S--l\/lBl;.

'lnia C1 O 0 O R HrOH O in water -0 O O R Thia 0 0 o 01 \oHflc 20 in ic solven -C 0 0 R SC O O R Tm L Thia CH2CH2OCOGI CHzCHzO-COOR' (III) (I) wherein R, R and Met. have each the same significance as designated above. As understood from the above formulae, the present process requires no basic catalyst. Accordingly, the objective O,S-disubstituted thiol-type thiamine derivatives (I) can be prepared in good yields with high purity.

The starting S-alkali metal salt of O-(a-tetrahydropyranyl)-thiamine (IV) is advantageously prepared by the following process: (1) reacting 3-halogeno-5-hydroxy-2- pentanone with 4H-dihydropyran in the presence of a mineral acid; (2) reacting the resultant 3-halogeno-5-(2- tetrahydropyranyloxy)-2-pentanone with N-(2-methyl-4- amino-S-pyrimidyl)-methyldithiocarbamic acid in the presence of a base; (3) treating the resulting 3-(2-methyl- 4 amino 5-pyrimidyl)-methyl-4-methyl-4-hydroxy-5-[2- (2 tetrahydropyranyloxy) ethyl]-thiazolidine-2-thione with a mineral acid in the presence of 4H-dihydropyran; (4) reacting the resultant o-(a-tetrahydropyranyl)-thiothiamine with hydrogen peroxide in the presence of barium ion at a pH between 3 and 6; and (5) treating the resulting O-(a-tetrahydropyranyl)-thiamine with an aqueous alkali hydroxide.

According to the present invention, the starting S- alkali metal salt of O-(wtetrahydropyranyl) thiamine (IV) is first reacted with an alkyl or alkenyl chlorocarbona-te in water. The reaction may be effected at room temperature (10 to 30 C.) or while heatnig. Then, the resultant 0-(m-tetra-hydropyranyl)-S-substituted thiol-ty-pe thiamine derivative (II) is reacted with phosgene in an inert organic solvent (e.g. benzene, toluene, ether, tetrahyd-rofuran, dioxane, chloroform, bromoform, dichloromethane, dichloroethane, trichloroethane, carbon tetrachloride). The reaction can proceed automatically with generation of beat. No cooling or heating is needed. The thus-prepared O-chlorocarbonyLS-substituted thioltype thiamine derivative (III) is then reacted with'an alkanol or alkenol. The reaction may be carried out 106 C. (decomp.)] through O-(wtetr ahydropyranyl)- at a temperature from room temperature to refluxing S-ethoxycarbonylthiam-ine monohydrate and chlorocartemperature. As an a-lkano-l or alkenol can play a role bonyl-S-ethoxycarbonylthiamine hydrochloride. of a solvent as well as a reagent, no other solvent is required. Although the present process has been herein-. 5 Example 3 above illustrated step by step, these steps may be effected s-m s-oooodn successively without isolation of the intermediary products. Thia Thia Presently preferred embodiments of the present invention are illustratively shown in the following examples. CHOHZO The relationship of parts by weight to parts by volume EPGOOCHD seoooclm is the same as that between grams and milliliters. Temperatures are set forth in degrees centi-grade.

E le 1 CHrCHzO-COGI ornoHzo-ooooi'm xamp In the same manner as shown in Example 1 (A), (B) and (C), S-sodium salt of O-(a-tetrahydropyranyl)-thi- Thia Thia amine is converted into O,S-di-n-butoxycarbonylthiamine \cgflomo hydrochloride monohydrate [M.P. '85 to 88 C.] through \0 0 O-(a-tetrahydropyranyl)-S-n-butoxycarbonylthiamine hys-oooom, s-ooooim drochloride [M.P. 125 C.] and O-chlorocarbonyl-S-n- Thia Th'ia butoxycarbonylthiamine hydrochloride. ouiouio-oooi oHzoHio.o00o,Hi Example 4 (A) To a solution of S-sodium salt of O-(a-tetra-hydro S COOC,Hg pyranyl)-t-hiamine (1.94 parts by weight) in water 20 y Tma Tm par-ts by volume), there is dropwise added ethyl chloro- 21) a carbonate (0.55 part by weight) while cooling with ice, GH2CH2O-\o O and the resultant mixture is stirred for 3 hours at room S COOG4Hu S COOO4HQ temperature (10 to C.). The reaction mixture is made T1 alkaline with ammonia and shaken with chloroform. The 1m 15 chloroform layer is dried over anhydrous sodium sulfate 30 0H1CH1O00C1 CH1CH2O-C00C2H: and the solvent evaporated. The residue is crystallized I th Same manner as Shown i E l 1 (A), (B) from ethanol to give O-(a-tetrabydropyranyl)-S-ethoxyand (C), S-sodium salt of O-(a-tetrahydropyranyl)-thicarbonylthiamine monohydrate Parts y weight) as amine is converted into O-ethoxycarbonyl-S-n-butoxycrystals melting at 73 to 74 C. carbonylthiamine hydrochloride semihydr-ate [M.P.

( To Ia 501110011 0f W- y Py yD 136 C. (decornp.)] through O-( -tetrahydropyranyD- Pxycarbonylthiamine monohydrate P Y weiglifll) S-n-butoxycarbonylthiamine hydrochloride and O-chloro- 111 chloroform Parts y there 18 p carbonyl-S-n-butoxycarb-onylthiamine hydrochloride. added a solution of phos'gene. (2.7 parts by weight) in toluene (6.3 parts by weight) while stirring whereby the 40 E p 5 reaction proceeds with generation of heat. The resulting S-Na s-COOCH2CI =OH2 mixture is stirred at room temperature (10 to 30 C.) for 1151/ Thja/ 3 hours and the solvent evaporated under reduced pressure to give O-chlorocarbonyl-S-ethoxycarbonylthiamine OHtOHzO CH2CH2O O hydrochloride (5 parts by weight) as acolorless resinous H CH=C-Hz S-GO OCI{2CI'I=CI{2 material onci3 T111a\ This, 2530 D 1770 1720 OHzCHzO-GOGI CI'I2CH20OOOC:H2GH=C1'I (C) O-chlorocanbonyl-S ethoxycarbonylthiamine hy- (A) To a solution of S-sodium salt of O-(a-tetrahydrodrochloride (5.4 parts by weight) is combined with anhypyranyD-thiamine (1.94 parts by weight) in water (20 drous ethanol (20 parts by volume) and heated at 50 parts by volume), there is dropwise added allyl chloro- C. for 1 hour. The reaction mixture is allowed tostand carbonate (0.61 part by weight) while cooling with ice,

overnight and concentrated under reduced pressure. The and the resultant mixture is stirred for 3 hours at room residue is dissolved in chloroform (150 parts by volume) temperature (10 to 30C.). The reaction mixture is and shaken with 15% hydrochloric acid (30 parts by made alkaline with ammonia and shaken with chlorovolume). The chloroform layer is dried over anhydrous form. The chloroform layer is dried over anhydrous somagnesium sulfate and the solvent evaporated. The dium sulfate and the solvent evaporated. The residue is residue is crystallized from ether and recrystallized from crystallized from hydrous ethanol to give O-(a-tetrahyacetone to give O,S-diethoxycarbonylthiamine hydrochlodropyranyl) S allyloxycarbonylthiamine monohydrate ride monohydrate (4.7 parts by weight) as crystals melt- (1.9 parts by weight) as crystals melting at 61 to 63 C. ing at 121 C. (decomp). (decomp) Exam le 2 V (B) To a solution of O-(u-tetrahydropyranyl)-S-allylp oxycarbonylthiamine monohydrate (4.5 parts by weight) S-Na /SCOOC2H5 in chloroform (50 parts by volume), there is dropwise Thia Thia\ 5 added a solution of phosgene (2.7 parts by weight) in T toluene (6.3 parts by weight) while stirring whereb the CHZCEHO o v Chemo 0 reaction proceeds with generation ofheat. The resrilting S COOC,H5 mixture is stirred at room temperature (10 to 30 C.) for 3 hours and the solvent evaporated to give O-chlorocar- Th1a\ M Thja bonyl S -allyloxycarbonylthiamine hydrochloride (5.2 z C CHCP10C00C4H9 parts by weight) as a colorless resinous material.

In the same manner as shown in Example 1 (A), ('B) (C) O-Chlorocarbonyl-S-allyloxycarbonylthiamine hyand (C), S-sodium salt of O-(a-tetrahydropyranyl)-thidrochloride (5.2 parts by weight) is combined with allyl amine is converted into O-n-butoxycarbonyl-S-ethoxycaralcohol (20 parts by volume), heated at 50 C. for 1 hour bonylthiamine hydrochloride monohydrate [M.P. 105 to and allowed to stand overnight. The reaction mixture is,

N-CH

CHO

S-Met.

0 a OHzCHaO wherein Met. is an alkali metal with a member selected from the group consisting of alkyl chlorocarbonate and alkenyl chlorocarbonate in water, reacting the resultant O-(a-tetrahydropyranyl) S substituted thiol type thiamine derivative of the formula:

N=GNH2 CHO wherein R is a member selected from the grou consisting of alkyl having not more than five carbon atoms and alkenyl having not more than five carbon atoms with phosgene in an inert organic solvent and reacting the resulting O-chlorocarbonyl S substituted thiol-type thiamine derivative of the formula:

wherein R has the same significance as :designated above with a member selected from the group consisting of alkanol and alkenol to give the O,S-disubstituted thioltype thiamine derivative of the formula:

N-CH

wherein R is a member selected from the group consisting of :alkyl having not more than five carbon atoms and alkenyl having not more than five carbon atoms and R has the same significance as designated above.

2. Process for preparing O,S-diethoxycarbonylthiamine which comprises reacting S-sodium salt of O-(u-tetrahydropyranyD-thiamine with ethyl chlorocarbonate in water, reacting the resultant O-(a-tetrahydr-opyranyI)S- ethoxycarbonylthiamine with phosgene in an inert organic solvent and reacting the resulting O-chlorooarbonyl-S- ethoxycarbonylthiamine with ethanol.

3. Process for preparing O,S-diallyloxycarbonylthiamine which comprises reacting S-sodium salt of O-(a-tetrahydropyranyl)thiamine with allyl chlorocarbonate in water, reacting the resultant O-(a-tetrahydropyranyl)S-allyloxycarbonylthiamine with phosgene in an inert organic solvent and reacting the resulting O-chlorocarbonyl-S-allyloxycarbonylthiamine with allyl alcohol.

4. A method for replacing the pyranyl group in a compound of the formula a CHzCHgO S-COOR by a COOR group, which comprises reacting the latter with phosgene in inert solvent medium, whereby the References Cited by the Examiner UNITED STATES PATENTS 3,158,613 11/1964 Takamizawa et al. 260-2565 FOREIGN PATENTS 944,641 12/ 1963 Great Britain.

OTHER REFERENCES Y-oshida: The Annual Report of Takamine Laboratory, vol. 13, 1961, pages 12-13.

ALEX MAZEL, Primary Examiner.

MARY U. OBRIEN, Assistant Examiner. 

1. PROCESS FOR PREPARING O,S-DISUBSTITUTED THIOLTYPE THIAMINE DERIVATIVES WHICH COMPRIES REACTING S-ALKALI METAL SALT OF O-(A-TETRAHYDROPYRANYL)-THIAMINE OF THE FORMULA: 